tbuckley/cabot-search huggingface dataset:
Frequency of loco-regional complications and their IMPACT on hospitalization outcomes in patients with cholangiocarcinoma.
Authors: Mihir Shah, Dennis Danso Kumi, Vaishali Deenadayalan, Rafaella Ferreira de Araujo Litvin, Mona Dasgupta, Ekrem Turk, Shweta Gupta
Journal: Journal of Clinical Oncology (2022)

e16135 Background: Cholangiocarcinomas, based on their anatomic location are prone to a myriad of local and regional complications. This study aims to explore if the outlook of patients differs based on what type of loco-regional complications they are admitted with. Methods: The National Inpatient Sample (NIS) was queried to identify adult patients with underlying cholangiocarcinoma between 2016-2018. Relative frequency and diagnosis of locoregional complications as principal diagnosis in these patients were identified and top 5 loco-regional complications were studied and compared for all-cause mortality, mean length of stay (LOS), mean total hospital charges (THC). Statistics were performed using t-test, univariate and multinomial logistic regression. Results: There were 26,410 hospitalizations in patients with cholangiocarcinoma. Upper gastrointestinal bleed (UGIB) represented the most frequent loco-regional complication (9.2%), followed by acute liver failure and cancer pain admission (6.7% each). Mortality rate of all admissions was 5.84%; all complications except failure to thrive were associated with significantly increased odds of mortality, the highest in acute liver failure (AOR- 3.72). Except admissions for cancer associated pain, all complications were associated with statistically significant increased LOS, highest in UGIB (Adjusted mean difference of 5 days). Similarly, admission with UGIB was associated with the highest THC while cancer pain admission had a much lower cost. Conclusions: Among the loco-regional complications of cholangiocarcinoma that were studied, UGIB was the most frequent, associated with longest hospital LOS (5 extra days) and highest THC. Admission with acute hepatic failure was associated with the highest odds of mortality while cancer associated pain and failure to thrive were associated with the shortest length of stay and lowest mean charges. Further efforts are needed to improve outpatient pain management to prevent these admissions and identify ways to improve outcomes in patients with UGIB. [Table: see text]
Discovering disparities in diffuse large B-cell lymphoma (DLBCL): A hispanic population comparison between Florida and Texas.
Authors: Ysaith Orellana, Carolina Velez-Mejia, Snegha Ananth, Qianqian Liu, Joel Michalek, Adolfo Enrique Diaz Duque
Journal: Journal of Clinical Oncology (2022)

e18562 Background: DLBCL is the most common type of non-Hodgkin lymphoma worldwide. Hispanics (H) in Texas (TX) and Florida (FL) represent 39.7% and 26.4% of the population of each state, respectively. This is the first population-based two statewide study looking at demographics, treatment patterns, and survival outcomes, in years (y), comparing those two Hispanic enriched states. We hope that identifying differences among state populations and provide interventions for the future. Methods: A retrospective cohort study of patients diagnosed with DLBCL between 2006-2017 using the Texas Cancer Registry and the Florida Cancer Data System. Standard demographic, socioeconomic, clinical, survival variables were reviewed. The Fisher's Exact tests and Chi-Square tests were assessed for categorical outcomes by ethnicity; Survival distributions were depicted using Kaplan-Meier curves. Results: From 2006 to 2017, 16,529 patients from TX and 18,641 patients from FL were diagnosed with DLBCL. At 20-100% poverty index, H in FL and TX had higher poverty percentages than non-Hispanic (NH), with TX H having the higher percentage (55%) compared to FL H (33%). Median survival time in FL was 5.4y for H compared to TX 3.7y H. Overall survival probability at 10y did show a statistically significant difference for H vs. NH when comparing FL (p &lt; 0.001) and TX (p = 0.95). Conclusions: In patients with DLBCL, two statistically significant differences were survival probability at 10y and median survival time comparing H populations in FL and TX. While most demographic variables were homogenous, one difference was observed; poverty index at 20-100% was higher for H in TX than FL. Higher poverty rates in TX to FL among the H population may explain why the median survival time and probability are higher and can provide further opportunities for structured interventions.[Table: see text] [Table: see text]
Antibiotics-free nanoparticles eradicate Helicobacter pylori biofilms and intracellular bacteria
Authors: Yiqing Zou, Xiaonan Chen, Yingying Sun, Pengyu Li, Mao Xu, Pengchao Fang, Shuqi Zhang, Gang Yuan, Xin Deng, Haiyan Hu
Journal: Journal of Controlled Release (2022)
Phase 1 study of SGN-PDL1V, a novel, investigational vedotin antibody–drug conjugate directed to PD-L1, in patients with advanced solid tumors (SGNPDL1V-001, trial in progress).
Authors: Amita Patnaik, Justin A Call, Anna Spreafico, Lisle Nabell, Mingjin Yan, Andres Forero-Torres, Maura L. Gillison
Journal: Journal of Clinical Oncology (2022)

TPS3154 Background: Programmed cell death ligand 1 (PD-L1) is a cell-surface protein involved in the programmed cell death protein 1 (PD-1)/PD-L1 immune checkpoint, which inhibits T-cell activation. Elevated PD-L1 expression is observed across a broad spectrum of solid tumor types. Expression of PD-L1 in tumors can signal through PD-1 on T cells to inhibit T-cell effector function. Blockade of the PD-1/PD-L1 signaling axis may restore antitumor immunity by reactivating T-cell effector function in the tumor microenvironment. SGN-PDL1V is a novel, investigational vedotin antibody–drug conjugate directed to PD-L1 with multiple proposed mechanisms of action including monomethyl auristatin E (MMAE)-directed cytotoxicity, bystander effect, and immunogenic cell death (ICD). Even in xenograft models with low, heterogeneous PD-L1 expression, SGN-PDL1V demonstrated antitumor activity via direct cytotoxicity and the bystander effect. Cytotoxicity mediated by SGN-PDL1V also led to immune activation due to MMAE-induced ICD (Kwan et al 2021). These preclinical findings provide a rationale for evaluating SGN-PDL1V in patients (pts) with advanced solid tumors. Methods: SGNPDL1V-001 (NCT05208762) is a phase 1, first-in-human, multicenter, open-label trial designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-PDL1V in pts with advanced solid tumors. This study includes 3 parts: dose escalation (Part A), dose and schedule optimization cohorts (Part B), and dose expansion in disease-specific cohorts and a biology cohort (Part C). Adult pts (≥18 years) with histologically/cytologically confirmed metastatic/unresectable solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, melanoma, or ovarian cancer, will be eligible. Pts must have ECOG PS 0–1 and have failed or are unable to tolerate standard therapies. Pts must have PD-L1 expression ≥1 by tumor proportion score or combined positive score based on historical testing. Prior treatment with an MMAE-containing agent or an anti–PD-L1 agent (within 6 months) is not permitted. Primary endpoints include adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative dose-level safety. Secondary endpoints include rate and duration of objective response, progression-free survival, overall survival, PK, and incidence of antidrug antibodies. Exploratory endpoints include pharmacodynamics (PD), PK/PD relationships, and patient-reported outcomes. Safety and antitumor activity endpoints will be assessed using descriptive statistics. Objective response rate will be analyzed by tumor type, dose levels, and schedules. Enrollment for Part A is ongoing at sites in North America and is planned in Europe. Clinical trial information: NCT05208762.
VEGFR-C mutation serves as a potential negative predictor for immunotherapy in metastatic melanoma.
Authors: Zhenguang Du, Qianru He, Xiaodan Xing, Qin Zhang, Qianqian Duan, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e21593 Background: Immune checkpoint blockade has shown significant promise as an anticancer treatment and anti–CTLA-4 treatment prolongs overall survival in patients with melanoma. Vascular endothelial growth factor-C (VEGF-C), a member of the VEGF gene family, has been characterised as a prime mediator of lymphangiogenesis and angiogenic growth factors that promote the growth and metastasis of neoplasms. Previous studies provided evidence that VEGF-C correlated with poorer survival in melanoma. We aimed to determine the association of VEGF-C mutations with melanoma survival to immune checkpoint inhibitors (ICI). Methods: Data from Allen study (n = 110, anti- CTLA-4 therapy) was obtained and analyzed. Meanwhile, we extracted skin cutaneous melanoma (SKCM) RNA data from The Cancer Genome Atlas (TCGA). In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Using the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm, the relative proportions of 22 types of infiltrating immune cells were determined in TCGA cohort. Results: In Allen cohort, the frequency of VEGFR-C mutation was 5.45% (6 in 110). Meanwhile, the frequency of VEGFR-C mutation in TCGA cohort was 7.37% (33 in 448). VEGFR-C-mutant (VEGFR-C-mut) group showed a poorer progression-free survival (PFS) (HR, 2.34; 95%CI, 1.01 to 5.4, p = 0.041) and overall survival (OS) (HR, 2.84, 95%CI, 1.22 to 6.62, p = 0.012) than the VEGFR-C-wild (VEGFR-C-wt) group, based on results of the log-rank test and Kaplan-Meier analysis. Moreover, COX proportional hazards model analysis showed VEGFR-C mutation was associated with poorer PFS (HR, 2.54; 95%CI, 1.04-6.25, p = 0.0042;) and OS (HR, 3.25; 95%CI, 1.30-8.12, p = 0.0117) compared with VEGFR-C-wt. In addition, we identified that the levels of naive B cells and resting CD4+ memory T cells were more abundant in VEGFR-C-mut group according to CIBERSORT algorithm. Conclusions: In our study, the frequency of VEGFR-C mutation in melanoma was investigated in Allen and TCGA cohorts, which might provide useful information to guide precision medicine. VEGFR-C mutation may serve as a potential negative predictor of response to anti-CTL4 treatment in melanoma via higher levels of naive B cells and resting CD4+ memory T cells.
Investigating the various predictive values of <i>TP53</i> mutations for response to immune checkpoint inhibitors (ICIs) in different solid tumors.
Authors: Xiaoguang Li, Xin Zhang, Yanling Niu, Tonghui Ma
Journal: Journal of Clinical Oncology (2022)

e14581 Background: TP53, a well-known tumor suppressor gene that encodes p53.The mutations of TP53 have been shown to be associated with higher tumor mutation burden (TMB). And patients with TP53 mutations are more likely to benefit from ICIs therapy. Previous studies have shown that TMB has divergent predictive value for response to ICIs therapy in different cancer types. We hypothesized that the associations between TP53 mutations and ICIs efficacy are also varied in different solid tumors. Therefore, we explored the prediction values of TP53 mutations in some cancer types. Methods: The ICIs treatment cohort from the Memorial Sloan Kettering Cancer Center (MSKCC) was selected to analyze the association of TP53 mutations with ICIs efficacy. The patients were classified into two groups: TP53 mutation (Mut) and wildtype (WT). Overall survival (OS) after ICIs therapy was estimated with the Kaplan-Meier method. Results: In MSKCC pan-cancer dataset, patients with TP53 mutations had significantly shorter median OS after ICIs therapy (14.00 vs 23.00 months, P &lt; 0.0001), indicating that TP53 mutations were associated with worse immunotherapy outcome. Then we analyzed the predictive roles in each cancer type. Notably, we found the associations of TP53 mutations with longer median OS in bladder cancer (27.00 vs 14.00 months, P = 0.0359). However, the associations between TP53 mutations and ICIs efficacy were not observed in breast cancer, esophagogastric cancer, glioma, head and neck cancer, melanoma, non-small cell lung cancer and renal cell carcinoma. We found the associations of TP53 mutations with shorter median OS in colorectal cancer (13.00 vs 34.00 months, P = 0.0368). Furthermore, the data showed that the median TMB was significantly lower in the Mut group for colorectal cancer (17.63 vs 35.98 muts/Mb, P = 0.0086) and higher in the Mut group for bladder cancer (14.25 vs 10.81 muts/Mb, P = 0.1588). Conclusions: Although TP53 mutations were associated with better ICIs efficacy in previous studies, the prolonged OS was only found in the Mut group for bladder cancer. Although TP53 mutations were associated with worse ICIs efficacy for all the enrolled patients, the poor outcome was only found in the Mut group for colorectal cancer. These data suggested that TP53 mutations may be a useful predictor for ICIs efficacy in these two types of cancer.
MODL-25. Radiation and focused ultrasound–mediated blood–brain barrier opening for DMG: safety and feasibility of combinatorial therapy
Authors: Nicholas McQuillan, Masih Tazhibi, Hong-Jian Wei, Antonios Pouliopoulos, Ethan Bendau, Andrea Webster Carrion, Alexander Berg, Danae Kokossis, Xu Zhang, Zhiguo Zhang, Zachary Englander, Nina Yoh, Chia-Ing Jan, Robyn D Gartrell, James Garvin, Luca Szalontay, Elisa Konofagou, Stergios Zacharoulis, Cheng-Chia Wu
Journal: Neuro-Oncology (2022)

Abstract Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic therapeutic strategies have been unsuccessful to date and radiotherapy (RT) remains the standard of care. A central impediment to systemic therapy is the blood-brain barrier (BBB), which precludes drug delivery to the tumor site. Focused ultrasound (FUS) with intravenous microbubbles can transiently and non-invasively circumvent the BBB to enhance drug delivery. Nevertheless, it remains unclear whether FUS is safe at the brainstem in combination with clinical doses of RT. In this study, we hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT. To establish a safety timeline, we administered FUS to the brainstem of nontumor bearing mice concurrent with or adjuvant to radiation; then, we validated our findings in a syngeneic orthotopic xenograft DMG model which received repeated sonication concurrent with RT. Male B6 (Cg)-Tyrc-2J/J albino mice received intracranial injection of 4423 mouse DMG cells (PDGFB+, H3.3K27M, p53−/−) at a location posterior and lateral to the lambda. A clinical RT dose of 39 Gy in 13 fractions was delivered to the brainstem with the Small Animal Radiation Research Platform (SARRP) or the XRAD-320 irradiator. FUS was administered with a 0.5 MHz transducer, and both BBBO and tumor volume were monitored with MRI. FUS-mediated BBBO in nontumor bearing mice receiving RT did not affect cardiorespiratory rate, motor function, and tissue integrity. Moreover, tumor bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy over 13 fractions offered local control, although disease progression occurred in all animals approximately 3-4 weeks post-RT. Ultimately, repeated FUS-mediated BBB opening concurrent with RT is safe and feasible. In our brainstem DMG model, relapse occurs, making it ideal for future tests of combinatorial RT and FUS-mediated drug delivery.
Characterization of NTRK alterations in metastatic colorectal cancer.
Authors: Canan Karan, Elaine Tan, Humaira Sarfraz, Christine Marie Walko, Richard D. Kim, Todd C Knepper, Ibrahim Halil Sahin
Journal: Journal of Clinical Oncology (2022)

e15569 Background: Increased molecular profiling ability has resulted in the recognition of important actionable genes that can be used to direct targeted therapies in colorectal cancers (CRC). Neurotrophin receptor tyrosine kinase (NTRK) gene fusions are one of these molecular alterations that are potentially actionable with novel targeted therapeutics. However, other biologically pathogenic NTRK alterations, including point mutations, are not yet actionable in CRC. This study aimed to characterize NTRK alterations, including fusions in metastatic CRC patients. Methods: Molecular characteristics of 917 patients with CRC were collected from the Moffitt Cancer Center Clinical Genomics Action Committee database. Demographic, clinicopathological, and molecular data and treatment history were abstracted from electronic medical records. Mutations with potential oncogenic activity are considered “potentially pathogenic”, while alterations with proven oncogenic activity such as fusions are considered “pathogenic”. Results: There were 917 patients with CRC from November 2013 to December 2021, and 77 of them had NTRK alterations excluding synonymous mutations (8.3%, 77/917). Six patients had potentially pathogenic NTRK alterations, including one NTRK rearrangement (0.6%, 7/917); however, only 1 patient had an actionable pathogenic NTRK1 fusion (0.1%, 1/917), while the others (70) were a variant of unknown significance (VUS). The majority of NTRK alterations were missense mutations (92%; 71/77). The NTRK1 fusion partner was LMNA and occurred in the setting of an MSI-H tumor (3.7%; 1/27). Among patients with pathogenic and potentially pathogenic alterations (N = 7), there was only 1(14%) patient who had low tumor mutation burden (TMB) (&lt; 10 mut/MB). Most patients were older than 50 years (70.1%, 54/77) and male (58.4%, 45/77). Thirty-six patients (46..7%) had right-sided tumor, while 41 patients (53.2%) left-sided. Across all NTRK alterations cohort, MSI-H was found in 10.3% (7/77), and POLE/POLD1 pathogenic mutations were seen in 6.4% (5/77) patients. Conclusions: NTRK gene fusion is a relatively rare event (&lt; 1%) in CRC, including the MSI-H subtype. The majority of NTRK alterations in CRC are VUS, and they are not actionable, and they tend to be seen in the tumors with high TMB (TMB &gt; 10). Hypermutator tumors cause frequent VUS alterations in the NTRK gene with unknown clinical relevance.
THER-01. Precision brain tumor therapy by AAV-mediated oncogene editing
Authors: Laura von Soosten, Janina Haar, Veronika Frehtman, Stefan Holderbach, Julius Upmeier zu Belzen, Michael Jendrusch, Konstantin Okonechnikov, Stefan M Pfister, Dirk Grimm, Barbara Leuchs, David Jones, Lena M Kutscher, Marc Zuckermann
Journal: Neuro-Oncology (2022)

Abstract Pediatric high-grade glioma is a heterogeneous group of highly malignant tumors of the central nervous system, with a median overall survival of less than two years after diagnosis, demanding novel treatment options. One innovative approach is gene therapy, which has so far been hampered for cancer treatment owing to the lack of a system targeting tumor cells specifically. To overcome this limitation, we established a novel strategy for gene therapy, combining tumor cell-specific adeno-associated virus (AAV) variants with oncogene-specific CRISPR-Cas nucleases. We screened 177 different Cas9/gRNA combinations targeting the genes encoding H3K27M or BRAFV600E, and identified highly specific nucleases that edited the oncogenic allele but left the respective WT loci intact, which we validated by PCR amplicon sequencing. Next, we intravenously injected an AAV library engineered to encode its own capsid DNA into mice harboring patient-derived xenograft tumors driven by H3K27M or BRAFV600E. After 21 days, we resected neoplasms and separated mCherry-labeled tumor cells from normal surrounding cells by fluorescence-activated cell sorting. Using the DNA from tumor cells as template, we generated a second AAV library, which was utilized in another round of in vivo selection. At the end of each screen, DNA from tumor cells, surrounding cells, and control tissues (liver and spleen) was analyzed by amplicon sequencing. Strikingly, we identified multiple AAV variants that were highly and recurrently enriched in the analyzed tumor tissues. We are currently validating these variants by intravenously injecting selected, GFP-encoding AAVs to tumor-bearing mice and by subsequently analyzing their distribution throughout the aforementioned tissues. We will combine oncogene-specific nucleases with these validated AAV variants and analyze their anti-tumoral efficacy in a preclinical setting. Furthermore, we plan to adapt this approach to allografted mice, evaluating its feasibility and efficacy in syngeneic models.
The advent of anti-PDL-1 antibodies in the treatment of advanced gastric carcinomas: A systematic review.
Authors: Mounica Vorla, Usman Ali Akbar, Aqsa Ashraf, Mounika Pusa, Saman Barham, Adil Khan, Daniya Sheikh, Ammar Yaser Dab, Shaheryar Qazi, Zeeshan Chaughtai, Faiz Anwer
Journal: Journal of Clinical Oncology (2022)

e16020 Background: The poor prognosis of systemic chemotherapy in advanced gastric adenocarcinoma (GC) and gastroesophageal (GE) carcinoma prompted the development of novel agents such as anti-PDL-1 antibodies, which have the potential to overcome drug resistance due to signaling pathway overlap. We study here the safety and efficacy of standalone and combination chemo-immunotherapy in the treatment of advanced GC &amp; GE Carcinomas. Methods: Following the PRISMA guidelines, we searched the literature on PubMed, Cochrane, Embase &amp; clinicaltrials.gov. A total of 300 articles were screened, and 7 studies were included. Results: With anti-PDL-1 inhibitors in phase III clinical trial, the overall survival (OS) was more remarkable in Chemotherapy (CTX) vs. Avelumab (AVE) (5 vs 4.6 mo). However, Nivolumab (NIVO 1mg and NIVO 3mg) significantly prolonged the OS when combined with Ipilimumab (IPI), but the grade &gt; 3 adverse events were reported more in NIVO1 and NIVO3 regimen. Similarly, Pembrolizumab (P) increased both OS and progression-free survival (PFS) when used alone and as combination therapy compared to chemotherapy alone, as illustrated in the table. Conclusions: The anti-PDL-1 inhibitors show promising data to treat advanced or relapsed GC or GE Carcinomas with favorable side effect profiles. However, there is further need for high-quality large prospective randomized clinical trials.[Table: see text]